Genetically diverse mouse models of SARS-CoV-2 infection model clinical variation and cytokine responses in COVID-19

Host genetics are a significant determinant of coronavirus disease 2019 (COVID-19)1. Animal models that reflect genetic diversity and a range of clinical outcomes observed in human populations are needed to understand mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection dynamics and disease2. Here, we report a mouse panel comprising the diverse genetic backgrounds of the Collaborative Cross (CC) founder strains crossed to C57BL/6J mice expressing the K18-hACE2 transgene3 that enables infection by SARS-CoV-2. Infection of CCxK18-hACE2 F1 progeny resulted in a spectrum of weight loss, survival, viral replication kinetics, histopathology, and cytokine profiles, some of which were sex-specific. Importantly, survival was closely associated with early type I interferon expression and a phased proinflammatory response distinct from mice with severe disease. Thus, dynamics of inflammatory responses observed in COVID-19 can be modeled in diverse mice that provide a genetically tractable platform for understanding antiviral immunity and evaluating countermeasures.